Expression of MMP-2, MMP-7, MMP-9, MMP-10 and MMP-11 in human astrocytic and oligodendroglial gliomas.

The members of the matrix metalloproteinase family (MMP) have the ability to degrade macromolecules of the extracellular matrix and are responsible for tumor invasion and infiltration, limiting the effectiveness of the neurosurgical resection of brain tumors. Among the glial brain tumors, astrocytomas and oligodendrogliomas are the most important tumor entities and require a different therapeutic approach. To determine the pattern of MMP expression in astrocytic and oligodendroglial tumors, sections of astrocytic and oligodendroglial differentiated glioblastomas (WHO grade IV), as well as of anaplastic oligodendrogliomas (WHO grade III) and anaplastic gemistocytic astrocytomas (WHO grade III) were immunostained for MMP-2, MMP-7, MMP-9, MMP-10 and MMP-11. MMP-7, MMP-10 and MMP-11 were strongly expressed by neoplastic gemistocytic astrocytes while oligodendrocytic tumor regions showed only a low immunoreaction. In contrast, MMP-2 and MMP-9 mainly immunolabeled vascular structures. These data indicated that MMP-7, MMP-10 and MMP-11 contribute to the worse prognosis of astrocytic tumors when compared to oligodendrogliomas, while MMP-2 and MMP-9 might play an important role in neo-angiogenesis and tumor vascularization.

Extracerebral subdural manifestation of Chester-Erdheim disease associated with a giant adenoma of the pituitary.

Chester-Erdheim disease is a rare non-Langerhans histiocytosis, affecting within the CNS mainly the neurohypophyseal unit, the retrobulbar space and the parenchyma of cerebellum, cerebrum and brainstem. Here we present a case of a 55-year-old woman who developed an exophthalmus, edema and dyspnea, finally leading to death 4 months post admission to the hospital. A cMRI showed a retrobulbar fibrosis, a tumor in the sella turcica, and further tumor formation expanding from the pons to the spinal cord, but without involvement of the dural sheet. Autopsy revealed multiple tumors attached to the pituitary gland, the tentorium, and the brainstem as well as a diffuse thickening of the dura. Histologically, the tumor tissue consisted of densely packed lipid-laden foamy macrophages positive for CD68 and intervening fibrillary cords. Interestingly, tumor cells did not infiltrate/affect the parenchyma but showed a strictly extracerebral/ subdural location. In addition, sections of the pituitary tumor revealed a chromophobe giant adenoma of the pituitary gland. As to our knowledge this is the first detailed description of an exceptional case of intracranial CED presenting with strictly extracerebral/subdural tumor masses accompanied by a giant adenoma of the pituitary gland.

Locally reduced levels of acidic FGF lead to decreased expression of 28-kda calbindin and contribute to the selective vulnerability of the neurons in the entorhinal cortex in Alzheimer's disease.

Recent studies demonstrate that a disturbed calcium-homeostasis leading to increased susceptibility to excitotoxic triggers plays a major role in the neurodegenerative process initiating in layer 2 of the entorhinal cortex (EC2) during Alzheimer's disease (AD). Thus, proteins binding free Ca++ (i.e. calbindin) and factors regulating these proteins are of great importance for the neuroprotective-neurotoxic balance in the affected brain regions. In the present combined human and in vitro study evidence is provided that altered levels of the acidic fibroblast growth factor (aFGF) and calbindin expression are concomitantly present in EC2 neurons and have interactive effects. A dramatic loss of aFGF- and calbindin-labeled EC2 neurons was found. Further analysis of the surviving EC2 neurons revealed a strong immunoreactivity to calbindin and aFGF. In vitro experiments show that aFGF regulates calbindin expression, because treatment of differentiating neurons with recombinant aFGF increases calbindin expression in a time-dependent fashion. The data imply that a reduced expression of aFGF in EC2 neurons of AD brains leads to lower levels of calbindin resulting in decreased neuroprotective capacity.

Evidence for neuroprotective effects of acidic fibroblast growth factor in Alzheimer disease.

Recent studies indicate that fibroblast growth factors (FGFs) might confer neuroprotection against excitotoxicity. Therefore, the fact that acidic FGF (aFGF) is more abundant in motoneurons than in the hippocampal formation suggests that aFGF contributes to the selective vulnerability of neurons in entorhinal cortex (EC) in Alzheimer disease (AD). In order to understand the role of aFGF in AD, patterns of aFGF FGF receptor (FGFR), and N-methyl-D-aspartate (NMDA) receptor (NMDAR) expression in the EC and hippocampus of AD and control cases were investigated, and effects of aFGF on excitotoxicity were examined in vitro. In AD, the number of aFGF immunolabeled neurons was decreased in EC, while the remaining neurons showed significantly higher aFGF immunoreactivity. This latter group of neurons did not show cytoskeletal abnormalities. Acidic FGF and FGFR immunoreactivity were positively correlated, whereas a negative correlation was found between aFGF and NMDAR expression. These results were confirmed in vitro utilizing NT2N cells. Higher levels of FGFR protein were expressed in aFGF-treated cells, while less NMDAR protein was found compared with untreated cells. Furthermore, exposure of treated and untreated NT2N cell to glutamate revealed that aFGF can prevent glutamate induced cell death. Taken together these data suggest that aFGF regulates the expression of NMDAR and FGFR and thereby contributes to neuroprotection against glutamate excitotoxicity. Therefore, altered patterns of aFGF immunoreactivity in EC in AD are an important marker for selective vulnerability of EC neurons.

nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer's disease.

Nitric oxide is a multifunctional molecule that acts as messenger/modulator in synaptogenesis and potential neurotoxin and is synthesized by three isozymes of Nitric oxide synthase (NOS). The role of NOS in Alzheimer's disease (AD) is unclear. For example, neurons in the entorhinal cortex (EC) that are highly vulnerable to neurodegeneration in AD express low levels of NOS and while it has been suggested that the inducible form of NOS is upregulated in AD, it is still not clear if the constitutive expressed isozyme (nNOS) is involved in the process of neurodegeneration. In order to better understand the role of nNOS in the pathogenesis of AD, sections from the EC and hippocampus (HC) of AD and control cases were immunohistochemically analyzed by single- and double-immunolabeling using antibodies against nNOS and PHF-tau. Semiquantitative assessment of numbers of nNOS expressing neurons in different areas of the HC and EC showed a remarkable loss of nNOS expressing neurons in the entorhinal cortex layer II and--less severe--CA1 and CA3 of the hippocampus in patients with AD. In addition, double-immunolabeling studies revealed that nNOS is strongly associated with neurofibrillary tangles and plaques. These findings indicate that nNOS expressing neurons are highly susceptible to neurodegeneration and that nNOS might contribute to the pathogenesis of AD.

Alterations in glutamate receptor 2/3 subunits and amyloid precursor protein expression during the course of Alzheimer's disease and Lewy body variant.

Alterations in the processing and patterns of trophic and/or toxic factors might lead to the increased neuronal vulnerability in the entorhinal cortex in Alzheimer's disease (AD) and Lewy body variant (LBV). Therefore, patterns and levels of amyloid precursor protein (APP) and glutamate receptor (gluR) expression in the entorhinal cortex and hippocampus in relation to disease severity were investigated. Sections from the hippocampus and entorhinal cortex were single and double immunolabeled for APP, gluR2/3, and N-methyl-D-aspartate receptor (NMDA-R). Within the hippocampus and entorhinal cortex, image analysis revealed progressively decreased APP and gluR2/3 levels during the course of AD and LBV, whereas levels of NMDA-R were unaltered. Furthermore, the present study showed a positive correlation and close co-localization of APP and gluR2/3 immunoreactivity in neurons, suggesting a possible interaction between these two factors. In conclusion, these data imply that alterations in neuronal APP and gluR2/3 expression in the entorhinal cortex lead to increased susceptibility to neurodegeneration and might be markers of vulnerability.